The major goal of this project is the elucidation of SIV pathogenesis in experimentally- infected macaques, utilizing strains derived from sooty mangabeys (SIVsm) and African green monkeys (SIVagm). A SIVagm strain (SIVagm9063) which induces immunodeficiency in experimentally infected pig-tailed (PT) macaques was isolated. An infectious, molecular clone of this isolate also induced AIDS in PT macaques, whereas, inoculated rhesus (RH) macaques and AGM, the natural host, remained healthy. Significant differences in virus load were observed during primary infection of PT macaques, RH macaques and AGM by this cloned virus. A large burst of virus expression was observed during the primary infection of PT macaques, whereas virus levels were significantly lower in RH or AGM. These data suggest that species-specific virulence is associated with the extent of in vivo viral replication. With respect to SIVsm strains, a SIVsmE543 clone was derived from a highly pathogenic isolate of SIV from an immunodeficient RH macaque, E543. Like primary clinical isolates of HIV-1, this cloned virus appears to be resistant to neutralization in vitro by serum of monkeys that neutralized related laboratory strains of SIVsm with high efficiency. Two of four animals inoculated the SIVsmE543 cloned virus failed to seroconvert despite high viremia, and one of these animals was sacrificed with pneumonia at sixteen weeks. We have also pursued the study of SIV-infected macaques which were infected with either molecularly cloned SIVsm62d or uncloned SIVsmE660 but failed to develop AIDS. High primary viremia which persisted into the asymptomatic phase of infection was characteristic of animals that progressed to AIDS; low level of primary viremia with sustained control of virus level was observed in nonprogressors. Three of four SIVsmE660 nonprogressors had been immunized previously with a highly attenuated vaccinia virus (MVA)-SIV recombinant.